One third of Americans suffer from some form of chronic pain, (30% being resistant to analgesic therapy), making it a significant health problem with serious economic impact (estimated cost of approximately $100 billion annually). Chronic pain associated with complex regional pain syndromes is particularly difficult to manage. Chronic pain associated with inflammatory diseases such as rheumatoid arthritis is often difficult to treat in the clinic due to insufficient understanding of the nociceptive pathways involved. Current drug regimens are marginally effective and often display unacceptable side effects. Over the past decade, our multidisciplinary team has produced experimental results which clearly implicate the overproduction of peroxynitrite as a key mediator of inflammatory and chronic pain states in addition to the development of morphine-induced hyperalgesia and antinociceptive tolerance. Thus, the direct scavenging of this neurotoxic entity by small molecule drugs which act in enzyme-like catalytic fashion provides an unconventional approach to a completely novel analgesic strategy. The overriding goal is a broadly effective treatment for chronic pain associated with inflammatory diseases. Thus, a series of metal-charge-shielded metalloporphyrin and porphyrinoids with membrane penetration properties will be synthesized and screened as peroxynitrite decomposition catalysts. Pharmacokinetic and bioavailability studies will follow. Chemical entities displaying the highest catalytic activity with drug like properties will then be tested for analgesic efficacy and potency in 2 well established animal models of inflammation and arthritis While the main focus our research objective is in the transition of acute to chronic pain and therapeutic intervention to alleviate the chronic pain state, successful identification of orally active peroxynitrite decomposition catalysts will address numerous chronic disease states known to be driven by nitroxidative stress including diabetes, atherosclerosis and Parkinson's disease thus having major impact upon the quality of life for these patient populations. We have also shown that prototype catalysts act in a highly synergistic manner with subtherapeutic levels of selective COXII inhibitors, non-selective COX-I inhibitors, steroids, and methotrexate. Thus, through this approach we may be able to greatly lower the dosages of these important drugs for effective treatment of pain without or with greatly diminished side- effects. PUBLIC HEALTH RELEVANCE: The currently used drug regimens for the treatment of chronic pain associated with inflammatory diseases and arthritis, which encompass a number of varied mechanisms of action, are marginally effective and often display unacceptable side effects. Thus, a broadly effective treatment for chronic pain based upon the catalytic decomposition of the key neurotoxic species, peroxynitrite, would have wide-ranging beneficial effects for patients. In addition, the identification of orally active peroxynitrite decomposition catalysts will address numerous chronic disease states known to be driven by nitroxidative stress including diabetes, atherosclerosis and Parkinson's disease thus having major impact upon the quality of life for these patient populations.